Warning

Risk of HBV Reactivation in Patients Coinfected with HCV and HBV

HBV reactivation, including cases resulting in fulminant hepatitis, hepatic failure, and death, reported in patients coinfected with HCV and HBV who were receiving or had completed treatment with HCV direct-acting antivirals (DAAs) and were not receiving HBV antiviral therapy.125 (See Risk of HBV Reactivation in Patients Coinfected with HCV and HBV under Cautions.)

Test all patients for evidence of current or prior HBV infection before initiating sofosbuvir.125

Monitor patients coinfected with HCV and HBV for hepatitis flare or HBV reactivation during and after HCV treatment.125 Initiate appropriate management for HBV infection as clinically indicated.1

Introduction

Uses for Sofosbuvir

Chronic HCV Infection

Treatment of chronic HCV genotype 1, 2, 3, or 4 infection in treatment-naive (previously untreated) or previously treated adults without cirrhosis or with compensated cirrhosis, including those with HIV coinfection and those with hepatocellular carcinoma awaiting liver transplantation.1119

Treatment of chronic HCV genotype 2 or 3 infection in treatment-naive or previously treated pediatric patients ≥12 years of age without cirrhosis or with compensated cirrhosis.1

Must be used in conjunction with other antivirals;1119 do not use alone.1119

Used in multiple-drug regimen that includes sofosbuvir and ribavirin (with or without peginterferon alfa),1234511 multiple-drug regimen that includes sofosbuvir and simeprevir,121516119183 or multiple-drug regimen that includes sofosbuvir and daclatasvir (with or without ribavirin).8910119178

Specific multiple-drug treatment regimen and duration of treatment with sofosbuvir and other antivirals depend on HCV genotype and patient population.1

Treatment of chronic HCV infection is complex and rapidly evolving; consult a specialist to obtain the most up-to-date information.119 Information from the American Association for the Study of Liver Diseases (AASLD), Infectious Diseases Society of America (IDSA), and International Antiviral Society–USA (IAS–USA) regarding diagnosis and management of HCV infection, including recommendations for initial treatment, is available at [Web].119

Sofosbuvir Dosage and Administration

General

Must be used in conjunction with other antivirals;1 do not use alone.1

If adverse reactions potentially related to other antivirals in the multiple-drug regimen occur, adjust dosage (dosage modification) or discontinue these drugs according to respective manufacturer’s prescribing information.1 If other antivirals in the multiple-drug regimen are discontinued for any reason, sofosbuvir also should be discontinued.1

Administration

Oral Administration

Dosage

Pediatric Patients

Treatment of Chronic HCV Genotype 2 Infection

Sofosbuvir in Conjunction with Ribavirin

Pediatric patients ≥12 years of age weighing ≥35 kg without cirrhosis or with compensated cirrhosis (Child-Pugh class A): 400 mg once daily in conjunction with ribavirin for a duration of 12 weeks.1

Treatment of Chronic HCV Genotype 3 Infection

Sofosbuvir in Conjunction with Ribavirin

Oral

Pediatric patients ≥12 years of age weighing ≥35 kg without cirrhosis or with compensated cirrhosis (Child-Pugh class A): 400 mg once daily in conjunction with ribavirin for a duration of 24 weeks.1

Adults

Treatment of Chronic HCV Genotype 1 Infection

Sofosbuvir in Conjunction with Daclatasvir

Oral

Noncirrhotic: 400 mg once daily119 in conjunction with daclatasvir (60 mg once daily) for a duration of 12 weeks.119178

Compensated cirrhosis (Child-Pugh class A): 400 mg once daily119 in conjunction with daclatasvir (60 mg once daily).119178 Manufacturer of daclatasvir recommends a duration of 12 weeks.178 Experts recommend a duration of 24 weeks and state consider adding ribavirin to the sofosbuvir and daclatasvir regimen.119

Decompensated cirrhosis (Child-Pugh class B or C): 400 mg once daily119 in conjunction with daclatasvir (60 mg once daily) and ribavirin.119178 Usual duration is 12 weeks,119178 but optimal duration not established in those with cirrhosis.178 If regimen of sofosbuvir and daclatasvir (without ribavirin) used in patients who cannot receive ribavirin, experts recommend a duration of 24 weeks.119 Referral to an expert (ideally at a liver transplant center) recommended.119

Sofosbuvir in Conjunction with Peginterferon Alfa and Ribavirin

Oral

Treatment-naive without cirrhosis or with compensated cirrhosis (Child-Pugh class A): 400 mg once daily in conjunction with peginterferon alfa and ribavirin for a duration of 12 weeks.1

Sofosbuvir in Conjunction with Ribavirin

Oral

400 mg once daily in conjunction with ribavirin for a duration of 24 weeks;1 consider only in patients who cannot receive peginterferon alfa.1

Sofosbuvir in Conjunction with Simeprevir

Oral

400 mg once daily119 with simeprevir (150 mg once daily with food).119183 Continue both drugs for 12 or 24 weeks, depending on whether or not patient has compensated cirrhosis (Child-Pugh class A).119183 (See Table 1.) For patients with compensated cirrhosis, experts state consider adding ribavirin to the 24-week regimen of sofosbuvir and simeprevir.119

Treatment of Chronic HCV Genotype 2 Infection

Sofosbuvir in Conjunction with Daclatasvir

Oral

Noncirrhotic or with compensated cirrhosis (Child-Pugh class A): Some experts recommend 400 mg once daily in conjunction with daclatasvir (60 mg once daily).119 These experts recommend treatment duration of 12 weeks in those without cirrhosis and a duration of 16–24 weeks in those with compensated cirrhosis.119

Decompensated cirrhosis (Child-Pugh class B or C): Experts recommend 400 mg once daily in conjunction with daclatasvir (60 mg once daily) and ribavirin for a duration of 12 weeks.119 Referral to an expert (ideally at a liver transplant center) recommended.119

Sofosbuvir in Conjunction with Ribavirin

Oral

Treatment-naive or previously treated (i.e., failed interferon-based regimen with or without ribavirin) without cirrhosis or with compensated cirrhosis (Child-Pugh class A): 400 mg once daily in conjunction with ribavirin for a duration of 12 weeks.1

Treatment of Chronic HCV Genotype 3 Infection

Sofosbuvir in Conjunction with Daclatasvir

Oral

Noncirrhotic: 400 mg once daily119 in conjunction with daclatasvir (60 mg once daily) for a duration of 12 weeks.119178

Compensated cirrhosis (Child-Pugh class A): 400 mg once daily119 in conjunction with daclatasvir (60 mg once daily) and ribavirin.119178 Usual treatment duration is 12 weeks, but optimal duration not established.178 Experts recommend a duration of 24 weeks and state that use of sofosbuvir and daclatasvir without ribavirin can be considered.119

Decompensated cirrhosis (Child-Pugh class B or C): 400 mg once daily119 in conjunction with daclatasvir (60 mg once daily) and ribavirin.119178 Usual duration is 12 weeks, but optimal duration not established.178 Referral to an expert (ideally at a liver transplant center) recommended.119

Sofosbuvir in Conjunction with Ribavirin

Oral

Treatment-naive or previously treated (i.e., failed interferon-based regimen with or without ribavirin) without cirrhosis or with compensated cirrhosis (Child-Pugh class A): 400 mg once daily in conjunction with ribavirin for a duration of 24 weeks.1

Treatment of Chronic HCV Genotype 4 Infection

Sofosbuvir in Conjunction with Daclatasvir

Oral

Decompensated cirrhosis (Child-Pugh class B or C): Some experts recommend 400 mg once daily in conjunction with daclatasvir (60 mg once daily) and ribavirin for a duration of 12 weeks.119 If a regimen of daclatasvir and sofosbuvir (without ribavirin) used in patients who cannot receive ribavirin, experts recommend a duration of 24 weeks.119 Referral to an expert (ideally at a liver transplant center) recommended.119

Sofosbuvir in Conjunction with Peginterferon Alfa and Ribavirin

Oral

Treatment-naive without cirrhosis or with compensated cirrhosis: 400 mg once daily in conjunction with peginterferon alfa and ribavirin for a duration of 12 weeks.1

Geriatric Patients

Cautions for Sofosbuvir

Contraindications

Because sofosbuvir must be used in conjunction with other antivirals, consider contraindications for all antivirals included in the multiple-drug regimen.1 (See Precautions Related to Multiple-drug Treatment Regimens under Cautions.)

Sofosbuvir used in conjunction with ribavirin or in conjunction with peginterferon alfa and ribavirin is contraindicated in women who are or may become pregnant and in male partners of pregnant women.1 (See Precautions Related to Multiple-drug Treatment Regimens under Cautions.)

Warnings/Precautions

Warnings

Risk of HBV Reactivation in Patients Coinfected with HCV and HBV

Postmarketing reports of reactivation of HBV infection when DAAs were used for treatment of HCV infection in patients with HBV coinfection;125 fulminant hepatitis, hepatic failure, and death reported in some cases.125

HBV reactivation (abrupt increase in HBV replication manifested as rapid increase in serum HBV DNA levels or detection of HBsAg in an individual who was previously HBsAg negative and anti-HBc positive) reported in patients with HCV and HBV coinfection receiving HCV treatment with a regimen that included HCV DAAs without interferon alfa.125 HBV reactivation usually occurred within 4–8 weeks after initiation of HCV treatment.25

HBV reactivation also reported in patients receiving certain immunosuppressant or chemotherapeutic drugs;1 risk of reactivation associated with HCV DAAs may be increased in such patients.1

Mechanism for HBV reactivation in coinfected patients receiving HCV DAAs unknown.25 Although HCV DAAs not known to cause immunosuppression, HBV reactivation in coinfected patients may result from a complex interplay of host immunologic responses in the setting of infection with 2 hepatitis viruses.25

Prior to initiating treatment with an HCV DAA, including sofosbuvir, screen all patients for evidence of current or prior HBV infection by measuring HBsAg, anti-HBs, and anti-HBc.125119 If there is serologic evidence of HBV infection, measure baseline HBV DNA level.25119

In all patients with evidence of current or prior HBV infection, monitor for clinical and laboratory signs (i.e., HBsAg, HBV DNA levels, serum aminotransferase and bilirubin concentrations) of hepatitis flare or HBV reactivation during and after treatment with HCV DAAs.125119 Initiate appropriate management for HBV infection as clinically indicated.1119

Advise coinfected patients to immediately contact a clinician if they develop any signs or symptoms of serious liver injury.25 (See Advice to Patients.)

When making decisions regarding HBV monitoring or HBV treatment in coinfected patients, consult a clinician with expertise in managing HBV infection.25119

In most reported cases, bradycardia occurred within hours to days after HCV treatment initiated in patients receiving amiodarone (also has been observed up to 2 weeks after initiation of HCV treatment) and resolved after HCV treatment discontinued.1 Mechanism for this adverse cardiovascular effect unknown.1

Patients who may be at increased risk for symptomatic bradycardia if amiodarone used concomitantly with regimen of sofosbuvir with another DAA include those also receiving a β-adrenergic blocking agent, those with underlying cardiac comorbidities, and/or those with advanced liver disease.

Concomitant use of amiodarone and regimen of sofosbuvir with another DAA not recommended.1

If there are no alternative HCV treatment options and regimen of sofosbuvir with another DAA must be used in a patient receiving amiodarone, advise patient about the risk of serious symptomatic bradycardia before initiating HCV treatment.1 Perform cardiac monitoring in an inpatient setting during first 48 hours of concomitant use of amiodarone and regimen of sofosbuvir with another DAA;1 heart rate monitoring should then be performed daily (outpatient or self-monitoring) through at least the first 2 weeks of concomitant use.1 Similar cardiac monitoring recommended in patients who discontinued amiodarone just prior to initiation of sofosbuvir with another DAA or if there are no other treatment options and amiodarone must be initiated in a patient already receiving sofosbuvir with another DAA.1

Interactions

Precautions Related to Multiple-drug Treatment Regimens

Sofosbuvir must be used in conjunction with other antivirals.1 Consider cautions, precautions, contraindications, and drug interactions associated with each drug in the multiple-drug regimen.1 Consider cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) for each drug.1

Do not use concomitantly with ledipasvir/sofosbuvir181 or sofosbuvir/velpatasvir.176

When used in conjunction with ribavirin,1 consider that ribavirin may cause fetal toxicity and/or death.349377 Extreme care must be taken to avoid pregnancy in female patients and female partners of male patients receiving a ribavirin-containing regimen.349377 Obtain a negative pregnancy test for female patients of childbearing potential immediately prior to initiating ribavirin;349377 perform pregnancy tests monthly during and for 6 months after ribavirin treatment is completed.349377 Women of childbearing potential (and their male partners) and male patients (and their female partners) must use at least 2 forms of effective contraception during and for 6 months after ribavirin treatment is completed.349377

Specific Populations

Pregnancy

Adequate data regarding use of sofosbuvir in pregnant women not available;1 animal studies did not reveal evidence of fetal harm.1

When used in conjunction with ribavirin,1 consider that ribavirin is contraindicated in pregnant women and male partners of pregnant women.349377 (See Precautions Related to Multiple-drug Treatment Regimens under Cautions and see Contraindications under Cautions.)

Lactation

Not known whether sofosbuvir or its metabolites distributed into human milk.1 Predominant metabolite (GS-331007) distributed into milk in rats;1 no apparent effects on the nursing pups.1

Consider benefits of breast-feeding and importance of sofosbuvir to the woman;1 also consider potential adverse effects on the breast-fed child from the drug or from underlying maternal condition.1

When used in conjunction with ribavirin,1 consider potential for adverse reactions to ribavirin in nursing infants and discontinue nursing or the ribavirin-containing regimen.349377 (See Precautions Related to Multiple-drug Treatment Regimens under Cautions.)

Pediatric Use

Safety and efficacy for treatment of HCV genotype 2 or 3 infection not established in pediatric patients <12 years of age or weighing <35 kg.1

Safety and efficacy for treatment of HCV genotype 1 or 4 infection not established in pediatric patients of any age.1

Adverse effects and pharmacokinetics of sofosbuvir in pediatric patients ≥12 years of age with HCV genotype 2 or 3 infection are similar to those in adults.1

Geriatric Use

No clinically important differences in efficacy in patients ≥65 years of age compared with younger adults.1

Hepatic Impairment

HCV-infected patients with hepatocellular carcinoma awaiting liver transplantation: Safety profile of sofosbuvir used in conjunction with ribavirin is similar to that observed in HCV-infected adults in clinical trials.1

Drugs Affecting Breast Cancer Resistance Protein

Specific Drugs

Drug

Interaction

Comments

Antiarrhythmic agents (amiodarone)

Amiodarone: Concomitant use with regimen containing sofosbuvir in conjunction with another DAA (e.g., ledipasvir, simeprevir) may result in serious symptomatic bradycardia123 (mechanism unknown);1 effect on amiodarone and sofosbuvir concentrations unknown1

Amiodarone: Concomitant use with regimen containing sofosbuvir with another DAA not recommended;1 if concomitant use required, patient counseling and cardiac monitoring required 1 (see Cardiovascular Effects under Cautions)

Oral contraceptive containing ethinyl estradiol and norgestimate: No clinically important effects on pharmacokinetics of ethinyl estradiol or norgestimate and its active metabolites (norelgestromin, norgestrel) when used concomitantly with sofosbuvir;113 efficacy of the oral contraceptive not expected to be affected13

Film-coated Tablets

Actions and Spectrum

Sofosbuvir is a prodrug that undergoes metabolic activation in the liver to a pharmacologically active uridine analog triphosphate (GS-461203), which can be incorporated into HCV RNA by NS5B polymerase; acts as RNA chain terminator.1

In replicon studies, the S282T substitution associated with reduced susceptibility to sofosbuvir did not affect susceptibility to ribavirin or HCV NS5A inhibitors.1 In addition, sofosbuvir was active against HCV replicons with substitutions associated with resistance to other drugs (e.g., ribavirin, HCV NS3/4A protease inhibitors).1

Advice to Patients

Importance of using sofosbuvir in conjunction with other antivirals;1 do not use alone.1

Advise patient not to reduce sofosbuvir dosage;1 if other antivirals in the multiple-drug regimen discontinued for any reason, sofosbuvir also should be discontinued.1

Inform patients that reactivation of HBV infection has occurred in coinfected patients being treated for HCV infection.125 Importance of informing clinician of any history of HBV infection or other liver problems (e.g., cirrhosis).125 Importance of immediately contacting a clinician if any signs or symptoms of serious liver injury (e.g., fatigue, weakness, loss of appetite, nausea and vomiting, yellowing of the eyes or skin, light-colored bowel movements) occur.25 (See Risk of HBV Reactivation in Patients Coinfected with HCV and HBV under Cautions.)

If regimen containing sofosbuvir with another DAA is used in a patient receiving amiodarone, advise patient about the risk of serious symptomatic bradycardia and importance of immediately contacting clinician if signs or symptoms of bradycardia (e.g., near-fainting or fainting, dizziness, lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pain, confusion, memory problems) occur.1 (See Cardiovascular Effects under Cautions.)

Inform patients that the effect of HCV treatment on transmission of HCV unknown;1 patients should take appropriate precautions to prevent transmission of the virus during treatment or in the event of treatment failure.1

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 If used in multiple-drug regimen that includes ribavirin, advise men and women of importance of using 2 forms of effective contraception during and for 6 months after ribavirin therapy.1 (See Precautions Related to Multiple-drug Treatment Regimens under Cautions.)

Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

119. American Association for the Study of Liver Diseases (AASLD). Recommendations for testing, managing, and treating hepatitis C. From the AASLD website. Accessed 2017 May 8. http://www.hcvguidelines.org

200. Panel on Antiretroviral Guidelines for Adults and Adolescents, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (July 14, 2016). Updates may be available at HHS AIDS Information (AIDSinfo) website. http://www.aidsinfo.nih.gov